(03427)Dicoumarol Alters Cellular Redox State and Inhibits Nuclear Factor Kappa B to Enhance Arsenic Trioxide-Induced Apoptosis

Ya-Wu JING, Jing
YI, Yu-Ying CHEN, Qing-Shen HU, Gui-Ying SHI, Hue LI, and Xue-Ming TANG*
(Department of Cell Biology, Shanghai Second Medical University, Shanghai
200025, China)

Abstract The effects of a
number of cytotoxic drugs are influenced by cellular reduction/oxidation (redox)
state. In the present study, we attempt to explore if dicoumarol, an inhibitor
of NADPH: quinone oxidoreductase (NQO1), alters the cellular redox state and
how this alteration affects the redox-related apoptosis. Flow cytometry was
used to assess the reactive oxygen species (ROS) level and apoptotic rates of
HeLa cells treated with arsenic trioxide (As₂O₃) alone
or in combination with natural anthraquinone emodin and dicoumarol or plus N-acetyl-cysteine.
Western blot, immunofluorescence, electrophoretic mobility shift assay and luciferase
assay were used to detect Nuclear Factor kappa B (NF-κB) activation. The results
showed that dicoumarol synergized with emodin to sensitize HeLa cells to As₂O₃-induced
apoptosis through raising the ROS level. More notably, this enhanced susceptibility
was associated with a ROS-mediated inhibition of NF-κB activation in which the
combinative treatment with dicoumarol prevented NF-κB from binding to target
DNA. It was suggested that dicoumarol in combination with anthraquinones might
be a novel strategy to expand the chemotherapeutic spectrum of As₂O₃
by means of interfering the cellular redox state.

Key words dicoumarol; arsenic
trioxide; reduction/ oxidation state; apoptosis; NF-κB

—————–
Received: November 13, 2003 Accepted:
January 6, 2004
This work was supported by the grants from National Natural Science Foundation
of China (No. 30170475) and Shanghai Education Committee (ZDXK2001).
*Corresponding author: Tel, 86-21-63846590-776421; E-mail, [email protected]